Dermatological composition and kit containing avermectin compound for treating dermatological conditions

ABSTRACT

A dermatological composition and a kit containing the composition for treating dermatological conditions including transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, acneiform eruptions, acne vulgaris, and seborrheic dermatitis are disclosed. The dermatological composition includes an avermectin compound in an effective amount to treat these dermatological conditions and a pharmaceutically acceptable carrier. The kit includes the dermatological composition integrated in medicated tape, topical dressing, dermal patch, or cleansing tissue.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of co-pendingApplication Ser. No. 10/159,938, filed on Jun. 3, 2002, which is acontinuation of Application Ser. No. 09/976,915 filed on Oct. 12, 2001,now U.S. Pat. No. 6,399,651, which is a continuation-in-part ofApplication Ser. No. 09/605,747 filed Jun. 29, 2000, now U.S. Pat. No.6,319,945; and further, this application is a continuation-in-part ofco-pending Application Ser. No. 10/161,585, filed on Jun. 3, 2002, whichis a continuation of Application Ser. No. 09/988,914 filed on Nov. 19,2001, now U.S. Pat. No. 6,399,652, which is a continuation in-part ofApplication Ser. No. 09/976,915 filed on Oct. 12, 2001, now U.S. Pat.No. 6,399,651, which is a continuation-in-part of Application Ser. No.09/605,747 filed Jun. 29, 2000, now U.S. Pat. No. 6,319,945. All priorapplications are herein incorporated by reference in their entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to a composition and a kitcontaining the composition for treating dermatological conditionsincluding transient acantholytic dermatitis, acne miliaris necrotica,acne varioliformis, perioral dermatitis, acneiform eruptions, acnevulgaris and seborrheic dermatitis.

BACKGROUND OF THE INVENTION

[0003] Transient acantholytic dermatitis, acne miliaris necrotica, acnevarioliformis, perioral dermatitis, acneiform eruptions, acne vulgaris,and seborrheic dermatitis are common dermatological diseases. Each hasits own etiology and histology.

[0004] 1. Transient Acantholytic Dermatosis

[0005] Transient acantholytic dermatosis, also called syn Grover'sdisease, is an acquired skin disease which is seen as itchy papules andvesicles resulting in soreness over the area. The lesions appear on theshoulders, neck, thighs, scalp rapidly. Some of the papules can becomerough and may have crusting. The disease mostly occurs in meddle to oldage, especially in men. Unlike the name of the disease, the condition isnot transient, and can last for years.

[0006] The cause of the disease is unknown, however, various factors arethought to precipitate the disease, including sun exposure and sun burn,heat exposure, sweating, fever, radiation treatment, and cancers. Thereis no specific treatment for this disease. Currently, topical steroids,systemic steroids, oral vitamin A, etretinate, PUVA (psoralen andlong-wave ultraviolet radiation) and Accutane® (isotretinoin,manufactured by Roche) have been used clinically.

[0007] 2. Acne Miliaris Necrotica and Acne Varioliformis

[0008] Acne miliaris necrotica, also called scalp folliculitis, consistsof follicular vesicopustules, frequently solitary, usually very itchyand tender, which appear anywhere in the scalp or adjacent areas. It canrange from an occasional nuisance that many people experience to achronic problem that can be quite troublesome. The severe form of thedisease which leaves large scars is called acne varioliformis. Thecondition is more common in people who are doing activities that makethem sweat or who wear occlusive head gear. Stress often seems totrigger outbreaks as well. Existing treatments range from antibioticshampoos such as Capitrol® (a chloroxine shampoo), astringentcompresses, topical antibiotics or steroids to oral antibiotics. Inextreme cases, Accutanee has been used, which is well known for thesevere adverse side effects that can cause.

[0009] 3. Perioral Dermatitis

[0010] Perioral dermatitis is a chronic papulopustular facialdermatitis. It mostly occurs in younger women. The incidence isestimated as 0.5-1% in industrialized countries, independent ofgeographical factors. The disease is limited to the skin. Skin lesionsoccur as grouped follicular reddish papules, papulovesicles andpapulopustules on erythematous base with a possible confluent aspect. Inan extreme variant of the disease, called lupuslike perioral dermatitis,granulomatous infiltrates occur with a yellowish aspect in diascopy.Although perioral dermatitis is limited to the skin and not lifethreatening, emotional problems may occur due to the disfiguringcharacter of the facial lesions and a possible prolonged course of thedisease.

[0011] The etiology of perioral dermatitis is unknown. However, manycausative factors have been suggested, including injudicious use oftopical steroids, fluorinated toothpaste, skin care ointments andcreams, especially with a petrolatum or paraffin base and the vehicleisopropyl myristate, and old or contaminated make-up or applicators. Itis known that UV light, heat and wind worsen perioral dermatitis.Further, microbials such as fusiform spirilla bacteria, candida speciesand other fungi have been found from the lesions. Other microbiologicalfactors, such as candidiasis have been reported to provoke perioraldermatitis. In addition, hormonal factors, and gastrointestinaldisturbances have been considered as well.

[0012] Known treatments include oral tetracyclines, minocin anddoxycycline, with discontinuing topical corticosteroids, and avoidinglauryl sulfate toothpaste. However, it is currently believed there is nomedicine that one can apply directly to the skin which will helpperioral dermatitis.

[0013] 4. Acneiform Eruptions

[0014] Acneiform eruptions are characterized by papules and pustulesresembling acne lesions, not necessarily confined to the usual sites ofacne vulgaris. The eruptions are distinguished by their sudden onset,usually in a patient well past adolescence. Most of the acneiformeruptions originate from skin exposure to various industrial chemicals.Some eruptions may come from oral medications. Acneiform eruptions maybe induced by exposure of the skin to the fumes generated in themanufacture of chlorine and its by-products. Cutting oils, lubricatingoils, crude coal tar applied to the skin for medicinal purposes, havetar distillates, coal tar pitch, and corticosteroids applied to the skinunder occlusive dressings, and asbestos are known substances that mayproduce acneiform eruptions. Some of the acneiform eruptions are inducedby medications such as iodides in vitamins with mineral supplement, andbromides in drugs such as propantheline bromide, and corticosteroids.

[0015] Although commonly called “trade acne”, “bromine acne”, and“chloracne”, acneiform eruptions are not a true acne, even though theyare often ushered in by open comedones. Current treatments of acneiformeruptions include massive keratinization-suppressing doses of vitamin A,300,000 units daily, topical retinoids, such as Retin-A cream or gel, oreven oral Accutane®.

[0016] The above-discussed dermatoses are commonly seen clinically. Somepatients respond well to the existing treatments. However, many patientssuffer from the diseases for many years without significant improvementafter being treated with all existing treatments. Furthermore, somepatients have adverse reactions to the existing medications, or can nottolerate antibiotics used for treating these dermatoses. Sometimes, itis not appropriate to use existing treatment methods or medications forcertain patients. For example, antibiotics and Accutane® are effectivefor treating acute inflammation caused by these dermatoses, however,they should not be used for pregnant women and nursing mothers.Therefore, there is apparently a need for new and effective topicaltreatments for the above-mentioned dermatoses.

[0017] 5. Acne Vulgaris

[0018] Acne vulgaris, known as acne by the general public, is a commonand multifaceted skin disorder of the hair follicles and sebaceousglands. Although it affects almost 100% of adolescents to varyingdegrees and generally wanes as adolescence ends, the disease may persistinto adulthood. Adult women, in particular, may be affected and mayexperience premenstrual flares. However, severe acne vulgaris tends tobe more common in adolescent males than in people of other age-groups.

[0019] At least four factors contribute to the development of acne:follicular plugging, increased sebum production by the sebaceous glands,colonization of the sebaceous follicles with Propionibacterium acnes,and inflammation. Propionibacterium acnes is the most commongram-positive, non-spore forming bacteria, a common resident of thepilosebaceous glands of the human skin. It is the causative agent ofacne vulgaris.

[0020] Follicular plugging occurs when desquamating cells lining thefollicular lumen stick together, rather than flowing to the surface withsebum. This occurs because of abnormal keratinization, components ofwhich are increased cell division and increased cohesiveness of cellslining the follicular lumen. These cells mix with sebum, plug theopening of the hair follicle, and form a closed comedo (commonly calledwhitehead). If this mixture protrudes from the follicular opening, itturns a dark color (blackheads).

[0021] During adolescence, when sebum production increases, thesebaceous follicles become colonized with Propionibacterium acnes. Thisanaerobic diphtheroid hydrolyzes sebum into free fatty acids, whichserve as the primary proinflammatory substances of acne vulgaris.Propionibacterium acnes also secrete chemotactic factors that attractneutrophils. Lysosomal enzyme released from the neutrophils rupture thefollicle wall releasing proinflammatory mediators including keratin andlipids into the surrounding dermis. The resulting inflammation formserythematous papules or pustules, nodules, cysts, or abscesses. If theinflammation is severe, as in cystic acne, the skin may eventually scar.

[0022] Therefore, the key features of the pathogenesis of acne vulgariscan be characterized as 1) increased sebum production, 2)hyperkeratinization of the neck of the follicles, 3) bacterialproliferation, and 4) inflammation. Acne vulgaris can be classified intothree categories: comedonal, inflammatory, and nodulocystic. Within eachcategory, acne vulgaris can be further divided into mild, moderate, orsevere, based on the number of lesions and the amount of skin involved.

[0023] Effective management of acne vulgaris can be accomplished byaddressing the four key features of the pathogenesis. Topical therapy isusually the first choice for patients with mild-to-moderate inflammatoryacne. The use of topical therapy minimizes potential side effectsassociated with the use of systemic agents. Topical therapies includebenzoyl peroxide, which is the most commonly used non-prescription acnemedication. It is an important antibacterial oxidizing agent that candecrease the number of Propionibacterium acnes and frequently the amountof free fatty acids. Benzoyl peroxide is the first line monotherapy formild acne vulgaris and it is available in over-the-counter preparations.Benzoyl peroxide is applied once or twice daily and patients oftenexperience mild redness and scaling of the skin during the first week ofusage.

[0024] Tretinoin is the most effective topical comedolytic agentcurrently, decreasing the cohesiveness of follicular epithelial cells,and thereby inhibiting the formation of microcomedones and increasingcell turnover resulting in expulsion of existing comedones. This agentalso decreases the thickness of the stratum corneum and potentiates thepenetration of topical antibiotic agents. Tretinoin therapy comprisesonce daily application. Mild redness and peeling are a part of thetherapeutic effect of the medication but can result in reduced patientcompliance. The improvement may take as long as 6 to 12 weeks, andflare-ups of acne vulgaris can occur during the first few weeks oftherapy.

[0025] Mild inflammatory acne vulgaris lesions can also be treated withtopical antibiotics including erythromycin ointment, clindamycinsolution, and meclocylcine cream. The primary action of the antibioticsis to reduce the population of Propionibacterium acnes in the sebaceousfollicle and thereby suppress the free fatty acid production. Theeffectiveness of topical antibiotics in the treatment of acne is limitedby their low lipid solubility and subsequent difficulty in penetratingsebum-filled follicles. Topical antibiotics are applied twice daily.

[0026] Patients with moderate to severe inflammatory acne often requireoral antibiotics in addition to topical therapy. The most commonlyprescribed agents include tetracycline, erythromycin, minocycline, anddoxycycline. Treatment is usually maintained for several months. Sideeffects include the overgrowth of nonsusceptible organisms, includingCandida, which can produce vaginal and oral yeast infections.

[0027] Patients with severe inflammatory acne vulgaris unresponsive toother therapy may require treatment with oral isotretinoin. Isotretinoinis a compound related to vitamin A, and is the only agent that decreasessebum production and reverses the abnormal epithelial formation process.This agent can also decrease number of Propionibacternum acnes in thesebaceous follicle. Duration of therapy is usually 20 weeks, and thesatisfactory response rate is quite high. However, treatment is oftenaccompanied by many side effects, including dry skin, pruritus,epistaxis, and photosensitivity, as well as hypertriglyceridemia,abnormal liver function tests, electrolyte imbalances, and elevatedplatelet counts. Most serious though, is the teratogeric effect ofisotretinoin. Use of isotretinoin during pregnancy is absolutelycontraindicated. So serious is the potential for death or teratogeniceffects to a fetus, isotretinoin is practically contraindicated in womenof child-bearing age. Use of isotretinoin must be accompanied by aguarantee by the patient that conception will be avoided at any and allcosts.

[0028] Because acne vulgaris is a multifactorial disease which ismanifest to varying degrees, it is important for the physician to assessthe patient to attempt to find therapies which will be helpful to thepatient without causing major side effects. All of the currentconventional treatments are associated with some degree of adverse sideeffects that limit their usefulness.

[0029] 6. Seborrheic Dermatitis

[0030] Seborrheic dermatitis, also known as seborrheic eczema andseborrhea, is a chronic superficial inflammatory disease of the skincapable of affecting many parts of the body including the scalp,eyebrows, nasolabial creases, lips, ears, sternal area, axillae,submammary folds, umbilicus, groins, and gluteul crease. The disease ischaracterized by many shapes, sizes, and surface textures and is oftencrust-like, yellowish, and accompanied by itching. This is alsocharacterized by remission and exacerbation.

[0031] The etiology, pathogenesis and histology of seborrheic dermatitisis unresolved. However, it bears close clinical resemblance to psoriasisand many researchers are of the belief that both conditions share arelated etiology, notwithstanding that psoriasis is a broader and lessdefinable condition. Therein, psoriasis typically differentiates overseborrheic dermatitis in its absence of itching and its resistancetreatment by compounds, such as, selenium sulfide and zinc pyrithionewhich have been employed in the treatment of seborrheic conditions.

[0032] The preferred compound that is used to illustrate the presentinvention is ivermectin. Ivermectin is a semi-synthetic derivative ofavermectin and is generally produced as a mixture of at least 80%22,23-dihydroavermectin B_(1a) and less than 20% 22,23-dihydroavermectinB_(1b). The following molecular structure represents the avermectinseries of compounds, which can be chemically converted to usefulderivatives as discussed below.

[0033] wherein R is the 4′-(alpha-L-oleandrosyl)-alpha-L-oleandrosegroup of the structure:

[0034] wherein the broken line indicates a single or double bond; R₁ ishydroxy and is present only when said broken line indicates a doublebond; R₂ is isopropyl or sec-butyl; and R₃ is methoxy or hydroxy.

[0035] The avermectins, of which ivermectin, a chemically producedanalog, is a member, are a series of compounds isolated from thefermentation broth of a C-076 producing strain of Streptomycesavermitillis and also chemically produced derivatives thereof. There areeight different but closely related compounds are produced by S.avermitillis, designated as A_(1a), A_(1b), A_(2a), A_(2b), B_(1a),B_(1b), B_(2a), and B_(2b). The production of these compounds isdescribed in U.S. Pat. No. 4,310,519. The preparation of ivermectin isdisclosed in U.S. Pat. No. 4,199,569. The disclosures of each of theforegoing patents are incorporated herein by reference. The avermectinfamily of compounds is a series of very potent antiparasitic agentsknown to be useful against a broad spectrum of endoparasites andectoparasites in mammals and also to have agricultural uses againstvarious nematode and insect parasites found in and on crops and in soil.

[0036] Some of the avermectins contain a 22,23-double bond. This may beselectively reduced to prepare the ivermectin compounds. In addition,the avermectins possess a disaccharide moiety at the 13-positionconsisting of the alpha-L-oleandrosyl-alpha-L-oleandrosyl group. One orboth of these saccharide groups may be removed as described in U.S. Pat.No. 4,206,205, and the produced aglycone derivatives have a hydroxygroup at the 13-position. This group may be removed to form the 13-deoxycompound as described in U.S. Pat. Nos. 4,171,314 and 4,173,571; thelatter patent also describes the 13-halo derivatives. The avermectincompounds and derivatives have several hydroxy groups which may beacylated as described in U.S. Pat. No. 4,201,861. U.S. Pat. No.5,055,454 describes invert position 13 of avermectin from a normal alphastereochemistry to the epimeric 13-beta stereochemistry. U.S. Pat. No.5,077,308 describes avermectin aglycone derivatives which incorporate aketal at position 13. U.S. Pat. No. 5,162,363 describes avermectinderivatives where te 23-position ring carbon atom is replaced with bysulfur atom. U.S. Pat. No. 5,229,416 describes avermectin aglyconederivatives which incorporate two fluorine atoms at position 13 and 23.U.S. Pat. No. 5,262,400 describes avermectin compounds that have varioussubstituents at the 4a-position including alkyl, alkoxy alkyl, orpolyalkoxy alkyl groups. Other derivatives of avermectin and ivermectinare disclosed in U.S. Pat. Nos. 4,333,925, 4,963,667, 5,114,930,5,350,742, and 5,830,875. All the aforementioned patents areincorporated herein by reference. The compounds disclosed in the patentsmentioned above share the property of antiparasitic activity withivermectin.

[0037] All avermectin compounds mentioned and referred to above sharethe spectrum of anti-parasitic biological activity of ivermectin,varying only in degree. It is expected that they will share the activityspectrum of ivermectin needed for them being suitable to use for thepurpose of the present invention.

[0038] Ivermectin has been used as an antiparasitic agent to treatvarious animal parasites and parasitic diseases since mid-1980's. It iscommercially available for animal use as Cardomec (for felines), Eqvalan(for equines) and Ivomec (for bovines) by Merial, a company of MerckSharp & Dohme and Aventis. The medicine is available in tablets andchewables for heartworm prevention, topical solution for ear mitetreatment, or as oral or injectable solution for other parasiteproblems.

[0039] Ivermectin is also commercially available from Merck & Co., Incfor human use as Stromectol® for eradication of threadworm Strongyloidesstercoralis, and for eradication of Onchocerca volvulus. Stromectol® wasapproved by the U.S. Food and Drug Administration to treatnondisseminated intestinal threadworm (strongyloidiasis) in March 1997.Stromectol® has also been cleared by the U.S. Food and DrugAdministration to treat onchocerciasis, or river blindness. The medicineis available in tablets and is orally administered by the patients. Therecommended dose of Stromectol® for the treatment of intestinalstrongyloidiasis is a single oral dose, two 6 mg tablets for averageweight adults (200 micrograms per kilogram of body weight). Stromectol®can also be used in children who weigh 15 kg (33 lb.) or more, at a doseranging from ½ to 2 tablets.

[0040] Magda et al. Amer. J. Trop. Med. Hyg. 53(6) 1995 pp. 652-653describe a method of topical application of ivermectin to treat headlice. Ivermectin is found to have an absolute curative effect after asingle topical application.

[0041] U.S. Pat. No. 5,952,372 (to McDaniel) discloses a method oftreating a form of rosacea associated with the ectoparasite Demodex byorally administering or topically applying ivermectin to fill andeliminate Demodex Follicuorum mites from hair follicles in affectedskin. Such treatment results in cessation of the manifestations ofallergic and vasomotor responses to the organism that cause the symptomsand signs of rosacea.

[0042] U.S. Pat. No. 6,133,310 (to Parks) discloses a method of treatingacne rosacea by topically applying ivermectin to the affected areas.Acne rosacea is a different dermatological disease, in term of etiology,and/or histology, from transient acantholytic dermatitis, acne miliarisnecrotica, acne varioliformis, perioral dermatitis, and acneiformeruptions addressed in the present invention. Differential diagnosis isimportant for the patients to obtain an appropriate treatment andeffective prevention of their conditions.

SUMMARY OF THE INVENTION

[0043] Accordingly, it is an object of the present invention to providea dermatological composition and a kit containing the composition fortopically treating transient acantholytic dermatitis, acne miliarisnecrotica, acne varioliformis, perioral dermatitis, acneiform eruptions,acne vulgaris and seborrheic dermatitis.

[0044] In one embodiment, the present invention provides adermatological composition for topically treating dermatologicalconditions including transient acantholytic dermatitis, acne miliarisnecrotica, acne varioliformis, perioral dermatitis, acneiform eruptions,acne vulgaris and seborrheic dermatitis.

[0045] The dermatological conditions comprises an avermectin compound inan amount effective to treat transient acantholytic dermatitis, acnemiliaris necrotica, acne varioliformis, perioral dermatitis, acneiformeruptions, acne vulgaris, or seborrheic dermatitis; and apharmaceutically acceptable carrier. The concentration of the avermectincompound in the dermatological composition can be from about 0.05% toabout 8% (w/v). In a preferred embodiment, the concentration of theavermectin compound is in a concentration range from about 0.05% toabout 0.5% (w/v).

[0046] The avermectin compound includes avermectin, avermectinderivatives, ivermectin, or ivermectin derivatives. In a preferredembodiment, ivermectin is used.

[0047] The pharmaceutically acceptable carrier includes water, glycols,alcohols, lotions, creams, gels, emulsions, sprays, shampoos, soaps,body washes, facial cleanser, and facial masks.

[0048] In a further embodiment, the present invention provides a kit fortopically treating the dermatological conditions. The kit comprises adermatological composition comprising an avermectin compound in anamount effective to treat transient acantholytic dermatitis, acnemiliaris necrotica, acne varioliformis, perioral dermatitis, acneiformeruptions, acne vulgaris, or seborrheic dermatitis, integrated in oneform selected from the group consisting of medicated tape, topicaldressing, dermal patch, and cleansing tissue.

DETAILED DESCRIPTION OF THE INVENTION

[0049] The present invention relates to a dermatological composition fortreating transient acantholytic dermatitis, acne miliaris necrotica,acne varioliformis, perioral dermatitis, acneiform eruptions, acnevulgaris, and seborrheic dermatitis.

[0050] The avermectin compounds for the purpose of the present inventioninclude avermectin, avermectin derivatives, ivermectin, and ivermectinderivatives. The avermectin compound is preferably mixed with apharmaceutically acceptable carrier or a base which is suitable fortopical application to dermal tissues, to form a dermatologicalcomposition. Suitable examples of carrier or base include, but notlimited to, water, glycols, alcohols, lotions, creams, gels, emulsions,and sprays. Furthermore, the dermatological composition containing anavermectin compound can be integrated into topic dressing, medicatedtape, skin patch, also called dermal patch, and cleansing tissues.Additionally, the avermectin compound can be added into shampoo, soap,body wash, facial cleanser, and facial mask. Examples 1 to 3 providevarious topical dermatological compositions containing an avermectincompound for treatment of the above-referenced dermatologicalconditions.

[0051] In a preferred embodiment, ivermectin is used because it isreadily available commercially. The concentration of ivermectin in thedermatological composition for the purpose of the present invention canbe in a broad range from about 0.05% to 8% weight by volume (w/v). Ithas been found that a lotion or a cream containing ivermectin at aconcentration as low as 0.075% is clinically effective in treatingtransient acantholytic dermatitis, acne miliaris necrotica, acnevarioliformis, perioral dermatitis, acneiform eruptions, acne vulgrisand seborrheic dermatitis.

[0052] The treatment method using ivermectin dermatological compositionfor each of these dermatological conditions is similar. Preferably, inan initial treatment of these dermatological conditions the ivermectindermatological composition can be applied topically from one to severaltimes daily for a period of from about one week to several weeks, tosubstantially control the condition and clear the lesions. The initialdosage, including frequency of the topical application, ivermectinconcentration of the dermatological composition, and the length of theinitial treatment period can be determined depending on a specificdisease, severity of the disease, and the response of the patient to themedication. For example, acne miliaris necrotica is more difficult totreat, and it frequently requires an initial treatment of three weeks orlonger. While perioral dermatitis patients can respond to ivermectintreatment rapidly, and healing of lesions can occur in less than twoweeks. After the initial treatment, a maintenance dosage, that has lessfrequent application, and/or a dermatological composition with lessconcentration of ivermectin, can be used for maintaining the condition.

[0053] It has been found in an informal clinical trial using the methodof the present invention that topical application of ivermectin to skinaffected by transient acantholytic dermatitis, acne miliaris necrotica,acne varioliformis, perioral dermatitis, or acneiform eruptions has thefollowing advantageous properties: (1) it removes itching and skinirritation caused by these dermatological conditions; (2) it clears uplesions; (3) it is anti-inflammatory and controls inflammation of theaffected area; (4) it has antimicrobial property and controls dermalinfection of the affected area; and (5) it is safe and has no sideeffects observed in any body locations.

[0054] The choice of the ivermectin concentration, and the form of thedermatological composition for treatment of a particular condition ofthe above-referenced dermatological conditions can be made depending onthe type and severity of the diseases, location of the affected area,and form of the dermatological composition.

[0055] To treat most patients diagnosed with one of the above-mentioneddermatological conditions, a lotion containing about 0.05% to 0.2% ofivermectin can be used. In the case of treating acute conditions, a morepotent composition containing higher concentration of ivermectin can beused. On the other hand, for prolonged maintenance of certainconditions, a low concentration such as from about 0.05% to about 0.1%is preferred. Further, a low concentration of ivermectin should be usedfor pediatric patients.

[0056] It is known that some of the diseases, such as perioraldermatitis, the skin on the eyelids can be affected. To treat eyelids, ahigh concentration of the medicine should be avoided to preventirritation of the eyes. It is found that a 0.075% ivermectin lotion doesnot cause eye irritation when it is used on the face, around the eyes,or directly on the eyelids.

[0057] In the form of shampoo, soap, facial cleanser, and facial maskthe concentration of ivermectin is higher, such as about 2% to about 8%,because the medicine is not retained on the skin after rinsing, andtreatment time is short. On the contrary, in the forms of topicdressing, medicated tape, and dermal patch the medicine stays on thetreated area longer than other forms, therefore, the concentration ofivermectin can be lower.

[0058] The ivermectin shampoo is an appropriate form for treatingtransient acantholytic dermatitis, acne miliaris necrotica and acnevarioliformis, when the affected area is on the scalp. The medicatedshampoo can be particularly suitable for maintenance treatment, orprevention of break out for the patients who have chronical history ofthese diseases.

[0059] Optionally, a combination of different forms of topical treatmentcan also be used. For example, an ivermectin tape can be used in thenight, and an ivermectin cream or lotion can be used during the day. Theivermectin shampoo; soap, facial cleanser, and facial mask can be usedin combination with any of other topical applications.

[0060] The dermatological composition containing ivermectin can be soldas a kit wherein the composition is packaged in a container, such as aplastic container. Instructions on how to use the dermatologicalcomposition in accordance with the present invention are included on orassociated with the container, which provides detailed instructions fortreating transient acantholytic dermatitis, acne miliaris necrotica,acne varioliformis, perioral dermatitis, acneiform eruptions, acnevulgaris, or seborrheic dermatitis.

[0061] Although the inventor is not bound by any theoretical explanationas to why the composition and the method of the present invention areeffective in treating transient acantholytic dermatitis, acne miliarisnecrotica, acne varioliformis, perioral dermatitis, or acneiformeruptions, presentation of certain theoretical understanding may be ofvalue. Based on the clinical observations, it is believed that onereason for the efficacy of the composition and the method of the presentinvention is due in part to anti-microbial property of ivermectin.

[0062] Another possible reason for the efficacy of the composition andthe method of the present invention is that the ivermectindermatological composition has anti-inflammatory effect. It is believedthat ivermectin exerts an anti-inflammatory effect on the cells of thesebaceous gland unit, thus decreasing production of neutrophils andlymphocytes which contribute to inflammation.

[0063] Ivermectin has been used as an oral medication for treatment ofriver blindness in human caused by Onchocerca volvulus parasite sincelate 1980s. With an oral dosage of a moderate ivermectin concentration,this medicine is safe in human, without serious adverse side effects.Therefore, topical treatment of dermatological conditions usingivermectin dermatological composition and the method of the presentinvention is safe to human patients, which was demonstrated by theclinical examples described hereinafter. Furthermore, as discussedpreviously that a dermatological composition having ivermectinconcentration as low as 0.075% is clinically effective in treatingtransient acantholytic dermatitis, acne miliaris necrotica, acnevarioliformis, perioral dermatitis, acneiform eruptions, acne vulgaris,or seborrheic dermatitis. Such a low concentration is advantageousbecause it reduces risks of adverse side effects, and reduces thepossibility of triggering body's autoimmune responses.

[0064] Operating with the informed consent of the patients who hadsuffered from one of the above-mentioned dermatological conditions, andtheir conditions had failed to improve by using existing treatmentmethods or were not appropriate to use existing medications, thepatients were treated with the ivermectin dermatological composition andthe method of the present invention. Examples 4 to 12 illustrateclinical effectiveness of the method of the present invention.

EXAMPLE 1

[0065] A topical dermatological composition containing avermectincompound is obtained as follows.

[0066] Mix 0.15 g of ivermectin, manufactured by Merck & Co., Inc.,sufficiently with 100 ml of deionized water to make an aqueoussuspension, wherein the concentration of ivermectin is 0.15% (w/v).Sodium hydroxide and citric acid can be used to adjusted pH of thesuspension to about 7.

[0067] Other suitable composition can be made in accordance with Example1 which include ivermectin in the following concentrations: 0.05%,0.075%, 0.2%, 0.5%, and 1% (w/v).

EXAMPLE 2

[0068] A topical dermatological lotion containing avermectin compound isobtained as follows.

[0069] Mix 0.075 g of ivermectin, manufactured by Merck & Co., Inc.,sufficiently with 100 ml of Cetaphil® moisturizing lotion, manufacturedby Galderma Laboratories, Inc., to make an ivermectin lotion, whereinthe concentration of ivermectin is 0.075% (w/v).

[0070] Other suitable compositions can be made in accordance withExample 2 which include ivermectin in the following concentrations:0.05%, 0.1%, 0.2%, 0.5%, 1%, 4%, and 8% (w/v) in the base of Cetaphil®moisturizing lotion. Other compatible commercial available lotions canalso be used as a base or carrier.

[0071] The Cetaphil® moisturizing lotion is a carrier of the ivermectin,which contains purified water, glycerin, hydrogenated polyisobutene,cetearyl alcohol and ceteareth-20, macadamia nut oil, dimethicone,tocopheryl acetate, stearoxytrimethylsilane and stearyl alcohol,panthenol, farnesol, benzyl alcohol, phenoxyethanol, acrylates/C10-30alkyl acrylate crosspolymer, sodium hydroxide, citric acid.

EXAMPLE 3

[0072] A medicated shampoo containing avermectin compound is obtained asfollows.

[0073] Mix 3 g of ivermectin, manufactured by Merck & Co., Inc.,sufficiently with 100 ml of a shampoo to make an ivermectin shampoo,wherein the concentration of ivermectin is 3% (w/v).

[0074] Other suitable compositions can be made in accordance withExample 3 which include ivermectin in the following concentrations of2%, 5%, and 8% (w/v) in a base of shampoo.

EXAMPLE 4

[0075] A 76-year-old male patient presented with several week history ofpruritic papules on his chest and back. Topical steroids had no effect.A biopsy showed a papule with mild lymphocytic infiltration and focalareas of epidermal acantholysis. The patient was diagnosed withtransient acantholytic dermatosis.

[0076] The patient was treated with topical application of the 0.075%ivermectin lotion of Example 2 once to twice daily to wet skin for twoweeks, followed with topical application of the lotion once or twiceweekly at bed time. The patient was also instructed to stop soap bath,and use weak acetic acids to double rinse clothes to remove all soap.The patient's condition improved significantly in three weeks. Thepatient was instructed to continue the topical application of the lotiononce weekly as needed. In an over two year follow up, the patient hadmaintained remained symptom free.

EXAMPLE 5

[0077] A 63 year old male patient suffered “itchy red bumps” on chestand back persisting for several months. Topical cortisone did notimprove the condition. Physical examination found pink to red smoothpapules on the chest and back. A biopsy showed only lymphocytic dermalinflammation, no acantholysis was found. The patient was diagnosed withtransient acantholytic dermatosis. The patient was treated with topicalapplication of the 0.075% ivermectin lotion of Example 2 twice daily forten days, followed by twice weekly. The patient had nearly totalclearing at his four week follow up visit.

EXAMPLE 6

[0078] A 60 year old male had more than fifteen years history of tender“pimples” and sores of the vertex scalp. Many past therapies, includingmedicated shampoos, oral and topical antibiotics, were of little or noeffect. Physical examination found vesico-pustules, crusts and thinninghair on the vertex scalp. The patient was diagnosed with acne miliarisnecrotic.

[0079] The patient was treated with topically application of the 0.075%ivermectin lotion of Example 2 daily at bed time for three weeks, with adecreased sugar consumption in his diet.

[0080] The patient had no new lesions since the first week of treatment.After three weeks treatment, all old lesions were completely healed.

EXAMPLE 7

[0081] A 50 year old male patient had a long history of tender sores onthe vertex scalp, associated with hair loss. Physical examination foundtypical vesico pustules of acne miliaris of the vertex scalp, inaddition to crusts, excoriations and thinning hair.

[0082] The patient was treated topically with the 0.075% ivermectinlotion of Example 2 at bed time for three weeks. The patient's affectedskin was totally cleared in three weeks. A maintenance dose of topicallyapplying the ivermectin lotion twice weekly was suggested to the patientfor maintenance.

EXAMPLE 8

[0083] A 35 year old female patient had five year history of scalptenderness, associated with tender papules. Many prior therapies failedto treat the condition. The patient was diagnosed with acne miliarisnecrotica on the dorsal and vertex scalp.

[0084] The patient was treated topically with the 0.075% ivermectinlotion of Example 2 daily at bed time, and washed out in the morning forthree weeks. Three weeks later, all lesions were healed.

EXAMPLE 9

[0085] A 33-year-old female patient had six-month history of perioraldermatitis, which had its onset during the patient's pregnancy. Previoustreatment was withheld because of her pregnancy. At the time of herfirst visit after the delivery, she was nursing the newborn baby and hadtransmitted the dermatitis to the baby's lip.

[0086] In lieu of using antibiotics because the mother was nursing, atreatment of topical application of the 0.075% ivermectin lotion ofExample 2 was given to both mother and the infant daily at bedtime fortwo weeks. Thereafter, the treatment was reduced to twice weekly. Inthree weeks, the baby had a total clearing, and discontinued thetreatment. The mother had near total clearing, and continued thetreatment twice weekly for another three months to insure healing.

EXAMPLE 10

[0087] A 68-year-old male patient with persistent perioral scalypapules, was diagnosed with perioral dermatitis. Previously, the patienthad adverse reactions to the standard topicals used in this condition,such as benzoyl peroxide, sulfacetamide, Metrogel® from GaldermaLaboratories, Inc., and others. In addition, the patient did nottolerate oral antibiotics.

[0088] The patient was treated with topical application of the 0.075%ivermectin lotion of Example 2 daily for two weeks. After two weeks, thepatient had a total clearing except mild residual erythema, he wasecstatic with the results achieved.

EXAMPLE 11

[0089] A 35-year-old female patient had a many year history of firm,tender, or mildly pruritic papulo-nodules on the checks and chin. Pasttreatments, for acne, were totally ineffective. The patient wasdiagnosed with acneiform eruptions without specific etiology. Thepatient had no iodine or bromine exposure.

[0090] The patient was treated with topical application of the 0.075%ivermectin lotion of Example 2 daily at bedtime for two weeks, pluselimination of caffeine intake. Thereafter, the dose was reduced totopical application of the lotion twice a week. After four weeks, thepatient had near total clearing of the lesions.

EXAMPLE 12

[0091] A 36-year-old female patient had a many year history of firmannoying pink nodules of the face. The patient had no history of halogenuse. This patient previously used numerous acne lotions and oraltetracycline without effect. The patient was diagnosed with acneiformeruptions.

[0092] The patient was treated with topical application of the 0.075%ivermectin lotion of Example 2 daily at bed time for two weeks, followedwith topical application of the lotion twice a week. At the four-weekreturn visit, the patient had a total clearing of the lesions.

EXAMPLE 13

[0093] A 20 year old pregnant woman developed pustulocystic acne, onetype of acne vulgaris, during the latter months of pregnancy. Therapywas limited to topical treatment including benzoyl peroxide, Retin-A(tretinoin), and hydrocortisone lotion. In spite of these treatments,her condition continued to worsen even after delivery. The patient hadtwo large cysts on the right cheek which her physician had scheduled forsurgery. Oral antibiotics were not a choice of treatment because she wasnursing.

[0094] The patient was treated with topical application of the 0.075%ivermectin lotion of Example 2 daily at bed time. In three weeks, hercondition improved substantially, and the “cyst surgery” was cancelledbecause it was no longer needed. A maintenance dosage of topicalapplication of the lotion twice a week was instituted thereafter forfour weeks, and the patient had a total clearing.

EXAMPLE 14

[0095] A 12 year old girl had extensive comedo-pustular acne (anothertype of acne vulgaris) on the brow, nose and malar areas. She wastreated with Retin-A and benzoyl peroxide. The patient was verydistraught because of the redness, inflammation and pustulation. Forthis reason she was treated with topical application of the 0.075%ivermectin lotion of Example 2 once to twice daily, in addition to herexisting conventional treatments. Within two weeks, all of the rednessand pustules were gone. Retin-A therapy was continued to the residualcomedones.

[0096] In the informal trials, no adverse side effects orcontra-indications were observed among the patients. The patients had nocomplaints of skin irritation during the initial treatment, or prolongedmaintenance treatment. There was no report of increasing skinsensitivity. For the patients who applied the ivermectin lotiontopically on the eyelids where the lesions were, there was no eyeirritation observed.

[0097] While there has been shown and described the preferred embodimentof the instant invention it is to be appreciated that the invention maybe embodied otherwise than is herein specifically shown and describedand that, within said embodiment, certain changes may be made in theform and arrangement of the parts without departing from the underlyingideas or principles of this invention as set forth in the Claimsappended herewith.

What is claimed is:
 1. A dermatological composition for topicallytreating dermatological conditions comprising: (a) an avermectincompound in an amount effective to treat transient acantholyticdermatitis, acne miliaris necrotica, acne varioliformis, perioraldermatitis, acneiform eruptions, acne vulgaris, or seborrheicdermatitis; said effective amount being in a concentration range fromabout 0.05% to about 0.5% (w/v); and (b) a pharmaceutically acceptablecarrier.
 2. The dermatological composition of claim 1, wherein saidavermectin compound comprises avermectin, avermectin derivatives,ivermectin, or ivermectin derivatives.
 3. The dermatological compositionof claim 2, wherein said avermectin compound is ivermectin.
 4. Thedermatological composition of claim 3, wherein said ivermectin is in aconcentration of about 0.075%.
 5. The dermatological composition ofclaim 1, wherein said pharmaceutically acceptable carrier compriseswater, glycols, alcohols, lotions, creams, gels, emulsions, sprays,shampoos, soaps, body washes, facial cleanser, and facial masks.
 6. Adermatological composition for topically treating dermatologicalconditions comprising: (a) an avermectin compound in an amount effectiveto treat transient acantholytic dermatitis, acne miliaris necrotica,acne varioliformis, perioral dermatitis, acneiform eruptions, acnevulgaris, or seborrheic dermatitis; said effective amount being in aconcentration range from about 0.05% to about 8% (w/v); and (b) acarrier selected from the group consisting of shampoos, soaps, bodywashes, facial cleanser, and facial masks.
 7. A kit for topicallytreating dermatological conditions comprising a dermatologicalcomposition comprising an avermectin compound in an amount effective totreat transient acantholytic dermatitis, acne miliaris necrotica, acnevarioliformis, perioral dermatitis, acneiform eruptions, acne vulgaris,or seborrheic dermatitis, integrated in one form selected from the groupconsisting of medicated tape, topical dressing, dermal patch, andcleansing tissue.
 8. The kit of claim 7, wherein said effective amountis in a concentration range from about 0.05% to about 0.5% (w/v).
 9. Thekit of claim 8, wherein said avermectin compound comprises avermectin,avermectin derivatives, ivermectin, or ivermectin derivatives.
 10. Thekit of claim 9, wherein said avermectin compound is ivermectin.